The invention relates to a salt or cocrystal of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (component a) and at least one acid component (b1) or at least one acid component (b2), wherein the salt or cocrystal of component (a) and component (b2) is present in crystalline and/or amorphous form, a medicament comprising said salt or cocrystal as well as said salt or cocrystal for use in the treatment of pain.
3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compounds such as e.g. (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, which is also known as tapentadol (CAS no. 175591-23-8) are synthetic, centrally acting analgesics which are effective in the treatment of pain.
Tapentadol exhibits a dual mechanism of action, on the one hand as a μ-opioid receptor agonist and on the other as a noradrenaline transporter inhibitor. In humans, the affinity of tapentadol to the recombinantly produced μ-opioid receptor is 18-times less than that of morphine. However, clinical studies have shown the pain-alleviating action of tapentadol to be only two to three times less than that of morphine. The only slightly reduced analgesic efficacy with a simultaneously 18-times reduced affinity to the recombinant μ-opioid receptor indicates that the noradrenaline transporter inhibiting property of tapentadol also contributes to its analgesic efficacy. Consequently, it may be assumed that tapentadol has a similar analgesic efficacy to that of pure μ-opioid receptor agonists but has fewer of the side effects associated with the μ-opioid receptor. The compound can be used in the form of its free base or as a salt or solvate. The production of the free tapentadol base and its hydrochloride salt are known for example from EP-A 0 693 475.
Conventional formulations for oral administration of a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound such as tapentadol usually lead to rapid release of the active substance in the gastrointestinal tract, thereby leading to a rather rapid onset of its analgesic action. Subsequently, a rather rapid reduction in the action is observed. In order to achieve an effective analgesic action over a prolonged period of time, i.e. to ensure an adequately high concentration of the active substance in the patient's blood plasma, it is therefore necessary to administer the pharmaceutical composition comprising said active substance at relatively short time intervals. However, the need for frequent dosing may lead to errors in administration and to undesirable variations in the concentration of the compound in the blood plasma which could be detrimental to patient compliance and the therapeutic benefit, particularly when treating chronically painful conditions.
In order to overcome such disadvantages of conventional formulations, EP-A 1 439 829 suggests providing a delayed-release pharmaceutical composition suitable for oral administration comprising 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol or its hydrogen chloride salt by means of retardation, i.e. by means of a matrix, a coating or in a release system based on osmotic action. Since the hydrogen chloride salt of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol has a high solubility in water and aqueous media, the manufacture of such a delayed-release formulation by retardation is considered necessary in order to achieve a controlled release of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol subsequent to administration.
However, there is still a need for alternative administration forms comprising a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound such as tapentadol by which a controlled release of the active substance can be achieved. Further, there is a need for such administration forms which do not necessarily have to be formulated using additional means of retardation.